This is a competitive renewal for RO1 NS39156, which supports our studies of Narp (Neuronal activity-regulated pentraxin) and related neural pentraxins including NP1 and NPR. Narp is an immediate early gene that is transcriptionally up-regulated in brain neurons in response to patterns of synaptic activity that evoke neuronal plasticity. Our broad goal is to understand how pentraxins contribute to neural plasticity, and thereby reveal new molecular and cellular mechanisms important for learning and memory, and diseases of cognition. Previously, we demonstrated that Narp is secreted at excitatory synapses where it binds AMPA-type glutamate receptors (AMPAR), and enhances synapse formation. Studies over the past 5 years have provided insights into the molecular basis of Narp's ability to enhance synapse formation, and support a model of diffusion-capture that depends on Narp-AMPAR binding. Remarkably, neural pentraxins also mediate rapid removal of AMPAR from synapses during the process of long-term depression that is induced upon activation of group 1 metabotropic glutamate receptors (mGluR-LTD). These studies revealed a novel coupling of mGluR to the extracellular protease TACE, which cleaves NPR and accelerates AMPAR endocytosis. The actions of neural pentraxins to both increase and decrease synaptic strength are dependent on their ability to form physical associations with AMPAR, and Aim 1 will extend our analysis of this physical interaction. Narp is particularly abundant at excitatory synapses on inhibitory interneurons, and we find that homeostatic changes in the strength of these synapses in response to changes in network activity are dependent on Narp. These observations support a new cellular model of Narp function as an activity-dependent regulator of inhibitory pathways that control network excitability. This hypothesis will be examined in Aim 2. Aim 3 also explores a new direction for the function of neural pentraxins. In ongoing studies, we have discovered a molecular complex that includes mGluR, neural pentraxins, TACE and BACE. Like TACE, BACE functions to cleave the extracellular (or luminal) domain of transmembrane proteins, and is the rate-limiting enzyme in the cleavage of amyloid precursor protein (APP) to generate A?. We find that neural pentraxins regulate the activity of TACE/BACE toward APP. A mouse KO model that deletes Narp, NP1 and NPR shows enhanced generation of A?40/42, and deposition of insoluble A? and plaque. Experiments in Aim 3 will define the molecular basis of pentraxin-dependent A??generation, and examine the hypothesis that this pathway is central for both normal synaptic plasticity and of activity-dependent generation of A? that contributes to Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This proposal examines mechanisms that mediate long lasting changes to synapses that are important for learning and memory. The work focuses on a protein termed Narp (Neuronal activity-regulated pentraxin), which is rapidly up-regulated in neurons as they participate in information storage. Narp, and related pentraxins, bind AMPA type glutamate receptors at synapses and regulate their function. Proposed studies will define the molecular basis of the action of Narp, and its role in synaptic plasticity and diseases of cognition.